Use of prostane derivatives of formulate I and II for treatment of chronic polyarthritis

ABSTRACT

The invention relates to the use of prostane derivatives general formula I ##STR1## in which X 1  is a --CH 2  --CH 2  -- or trans --CH═CH--, 
     X 2  is a straight-chain or branched, saturated alkylene group with 1 to 6 carbon atoms, 
     X 3  is a --CH 2  --, 
     X 4  is a --CH 2  --, 
     X 5  is a --C.tbd.C--R 2  ; 
     R 1  is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 5 or 6 carbon atoms, or a phenyl group, 
     R 2  is a straight-chain or branched-chain, saturated or unsaturated alkyl group with 1 to 6 carbon atoms, 
     R 3  is a hydrogen atom or an acyl radical with 1 to 4 carbon atoms, and 
     R 4  is an --H; 
     in which the --O--R 3  group is in α- or β-position, and their salts with physiologically compatible bases, if R 1  indicates a hydrogen atom, for the production of a pharmaceutical agent for the treatment of chronic polyarthritis.

This application is filed under 35 U.S.C. 371 and claims priority ofPCT/DE93/00722 filed Aug. 9, 1993, and claims priority to FederalRepublic of Germany application P 42 27 788.4 filed Aug. 19, 1992.

The invention relates to the use of prostane derivatives for theproduction of a medicament for the treatment of an immunologic response.

BACKGROUND OF THE INVENTION

Several prostane derivatives and their production are described inpublication EP 0 011 591 (date of application: Oct. 18, 1979). Theseprostane derivatives are compounds that are derived from prostacyclin(PGl₂). They contain a methylene group instead of the 9-ether-oxygenatom in prostacyclin. Prostane derivatives are used for the treatment ofvarious diseases; in this connection the cardiovascular andthrombo-aggregation-inhibiting effect is clearly emphasized.

The use of prostane derivatives as medicaments is described in detail inEuropean publication EP 0 011 591: Lowering of peripheral, arterial, andcoronary vascular resistance, inhibition of platelet aggregation anddissolution of platelet thrombi, myocardial cytoprotection and thuslowering of systemic blood pressure without reducing cardiac output andcoronary blood circulation at the same time; treatment of stroke,prophylaxis and treatment of coronary heart disease, coronarythrombosis, myocardial infarction, peripheral arterial diseases,arteriosclerosis and thrombosis, treatment of shock, inhibition ofbronchoconstriction, inhibition of stomach acid secretion andcytoprotection of the mucous membrane of the stomach and intestines;anti-allergic properties, lowering of pulmonary vascular resistance andof pulmonary blood pressure, stimulation of renal blood circulation, useto replace heparin or as an adjuvant in the dialysis of hemofiltration,preservation of dried blood plasma, especially of dried blood platelets,inhibition of labor pains, treatment of gestational toxicosis,antiproliferative effect, and improvement of cerebral blood circulation.

Carbacyclin derivatives are listed in publications EP-0 055 208, EP-0099 538, and EP-0 119 949, which have indications similar to those ofthe above-mentioned prostane derivatives.

Publication EP 0 084 856 describes other prostane derivatives which wereproposed for use in inhibiting platelet aggregation, lowering systemicblood pressure, or treating gastric ulcers. In particular, beraprost ismentioned in it.

The use of prostane derivatives for the treatment of immunologicresponses is described in various publications. Thus, the treatment ofanti-allergic properties is mentioned in passing even in EuropeanPublication EP 0 011 591.

European Publication EP 0 055 208 describes, i.a., the anti-allergiceffect of carbacyclin derivatives.

In the publication by H. J. GRUNDMANN et al. (1992) J. Infect. Dis.1992, 165: 1-5, the use of a prostane derivative, namely iloprost, inthe treatment of septic shock is explained in detail.

In international patent application PCT/DE 92/00100 (date of applicationof the priority-justifying application: Feb. 12, 1991 in the FederalRepublic of Germany), treating AIDS and diabetes with the help ofprostane derivatives is mentioned. This application is prior law.

The K. SLIWA et al. (1991) publication Infection and Immunity, 59:3846-3848 deals with the treatment of cerebral malaria with iloprost.

SUMMARY OF THE INVENTION

It has now been found, surprisingly enough, that prostane derivativescan be used in the case of another indication.

The invention relates to a use of prostane derivatives of generalformula I or II ##STR2## in which X₁ is a --CH₂ --CH₂ --; trans--CH═CH-- or --C.tbd.C--,

X₂ is a straight-chain or branched, saturated alkylene group with 1 to 6carbon atoms,

X₃ is an --O-- or --CH₂ --,

X₄ is a --CH₂ -- or --[CH₂ ]₃ --,

X₅ is an --H or --C.tbd.C--R₂ ;

R₁ is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, acycloalkyl group with 5 or 6 carbon atoms, or a phenyl group,

R₂ is a straight-chain or branched-chain, saturated or unsaturated alkylgroup with 1 to 6 carbon atoms,

R₃ is a hydrogen atom, an acyl radical with 1 to 4 carbon atoms, or abenzoyl radical, and

R₄ is an --H or --CH₃ ;

in which the --O--R₃ group is in α- or β-position, and their salts withphysiologically compatible bases, if R₁ has the meaning of a hydrogenatom, for the production of a pharmaceutical agent for the treatment ofchronic polyarthritis.

X₂ stands for straight-chain or branched, saturated alkylene groups withi to 6 carbon atoms, for example, methylene, ethylene, propylene,isopropylene, and the methyl group is connected to the first or secondcarbon atoms of the ethylene, counting from group A: butylene,methylpropylene, ethylethylene, dimethylethylene, and the methyl orethyl group is connected as desired to the alkylene chain; pentyl,methylbutylene, dimethylpropylene, ethylpropylene, methylethylethylene,in which the methyl or ethyl group is connected as desired to thealkylene chain; hexylene, methylpentylene, dimethylbutylene,methylethylpropylene, in which the methyl or ethyl group is connected asdesired to the alkylene chain.

Alkyl group R₁ comprises straight or branched alkyl groups with 1 to 6carbon atoms, such as, for example, methyl, ethyl, propyl, butyl,isobutyl, tert-butyl, pentyl, neopentyl, hexyl.

Cycloalkyl group R₁ can contain 5 or 6 carbon atoms in the ring.

Alkyl group R₂ can consist of straight-chain or branched-chain,saturated or unsaturated alkyl radicals with 1 to 6 carbon atoms; thealkyl radicals are preferably saturated. For example, methyl, ethyl,propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, butenyl, isobutenyl,propenyl, pentenyl or hexenyl groups can be mentioned.

Acyl group R₃ can consist of a straight-chain or branched-chain acylgroup with 1 to 4 carbon atoms, such as, for example, acetyl, propionyl,butyryl, or isobutyryl.

The invention also relates to a process for the treatment of chronicpolyarthritis in humans and mammals that require such a treatment, wherethe treatment involves administration of a pharmacologically safe andeffective amount of the prostane derivatives according to formula I orII in humans and mammals.

Inorganic and organic bases, as they are known to one skilled in the artfor the formation of physiologically compatible salts, are suitable forforming salts with free acids. For example, there can be mentioned:alkali hydroxides, such as sodium and potassium hydroxide,alkaline-earth hydroxides, such as calcium hydroxide, ammonia, amines,such as ethanolamine, diethanolamine, triethanolamine,N-methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine, etc.B-cyclodextrin clathrate formation takes place according to EP 0 259468.

Chronic polyarthritis is a joint disease in which the synovial tissuehas a destructive effect on the matrix of the articular cartilage. Inthe synovial tissue and the synovial fluid of-patients with chronicpolyarthritis, there are activated cells which secrete cytokines such asTNF-α and Il-1. Both cytokines, TNF-α and Il-1, are able to induce theproduction of collagenase and other neutral proteases in synovialfibroblasts and chondrocytes that are located near the articularcartilage. These enzymes degrade proteoglycans and collagen, which leadsto destruction of the cartilage. (TNF-α=tumor necrosis factor-α;Il-1=interleuin 1).

Surprisingly enough, prostane derivatives are suitable for the treatmentof chronic polyarthritis. Previously, substances such as carboxylicacids (salicylates, arylacetic acids, fenamates, propionic acids),pyrazolones, and oxicams were used for treatment. (Handbook ofExperimental Pharmacology, 1979, Springer Verlag, Vol. 50/II, Editors:G. V. R. BORN et al., Chapter 30, Anti-Inflammatory Drugs, J. R. VANE,S. H. FERREIRA, Chapter 32, Classification of Antirheumatic Drugs, E. C.HUSKISSON, Chapter 37, M. K. JASANI).

The use of prostane derivatives according to the invention is preferredwith the above-mentioned general formula I in which

X₁ is a trans --CH═CH--,

X₂ is a straight-chain or branched, saturated alkylene group with 2 to 4carbon atoms,

X₃ is a --CH₂ --,

X₄ is a --CH₂ --,

X₅ is a --C.tbd.C--R₂ ;

R₁ is a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or phenylgroup,

R₂ is a straight-chain or branched-chain, saturated or unsaturated alkylgroup with 1 to 3 carbon atoms,

R₃ is a hydrogen atom or an acyl radical with 2 carbon atoms and

R₄ is an --H;

in which the --O--R₃ group is in α- or β-position, and their salts withphysiologically compatible bases, if R₁ indicates a hydrogen atom, forthe production of a pharmaceutical agent for the treatment of chronicpolyarthritis.

More preferred is the use of prostane derivatives according to theinvention with the above-mentioned general formula I in which

X₁ is a trans --CH═CH--,

X₂ is a methylethylene group, in which the methyl group is connected tothe first carbon atom of the ethylene group and the first carbon atom ofthe ethylene group is assigned to group A,

X₃ is a --CH₂ --,

X₄ is a --CH₂ --,

X₅ is a --C.tbd.C--R₂ ;

R₁ is a hydrogen atom or a methyl group,

R₂ is a methyl or ethyl group,

R₃ is a hydrogen atom or a formyl group and

R₄ is an --H;

in which the --O--R₃ group is in α- or β-position, and their salts withphysiologically compatible bases, if R₁ indicates a hydrogen atom, forthe production of a pharmaceutical agent for the treatment of chronicpolyarthritis.

Most preferred is the use of a prostane derivative according to theinvention having the above-mentioned general formula I in which

X₁ is a trans --CH═CH--,

X₂ is a methylethylene group, in which the methyl group is connected tothe first carbon atom of the ethylene group and the first carbon atom ofthe ethylene group is assigned to group A,

X₃ is a --CH₂ --,

X₄ is a --CH₂ --,

X₅ is a --C.tbd.C--R₂ ;

R₁ is a hydrogen atom,

R₂ is a methyl group,

R₃ is a hydrogen atom and

R₄ is an --H;

in which the OH group is in α- or β-position, and its salts withphysiologically compatible bases, for the production of a pharmaceuticalagent for the treatment of chronic polyarthritis.

This substance has the name "iloprost" and bears the systematicdesignation5-(E)-(1S,5S,6R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl]bicyclo[3.3.0]octen-3-ylidenepentanoic acid. It is the most preferred compound of this invention.

The invention further comprises the use of the preferred substancescicaprost, eptaloprost, ciprostene and/or beraprost and their salts forthe production of a pharmaceutical agent for the treatment of chronicpolyarthritis. The substances, including iloprost, are listed to showtheir structures in Table 1.

The invention further relates to the use of prostane derivativesaccording to the invention together with pharmacological adjuvants andvehicles that are physiologically compatible. Such substances aredescribed in Remington's Pharmaceutical Science, 15th ed., MackPublishing Company, Easton, Pa. (1980).

The production processes for some of the prostane derivatives accordingto the invention are described in detail in publication EP 0 011 591 orEP 0 084 856. However, the substances of formula I or II that are notexpressly mentioned there do not differ as regards the productionprocess. They can be produced by one skilled in the art in the contextof general knowledge.

                                      TABLE 1                                     __________________________________________________________________________    Structures of the Preferred Prostane Derivatives                                    Formula                                                                 Designation                                                                         I or II                                                                            X.sub.1 X.sub.2 X.sub.3                                                                            X.sub.4                                                                             X.sub.5  R.sub.1                                                                          R.sub.2                                                                              R.sub.3                                                                         R.sub.4            __________________________________________________________________________    Iloprost                                                                            (I)  CHCH                                                                                   ##STR3##                                                                             CH.sub.2                                                                           CH.sub.2                                                                            C CR.sub.2                                                                             H  CH.sub.3                                                                             H H                  Cicaprost                                                                           (I)  C C                                                                                    ##STR4##                                                                             O    CH.sub.2                                                                            C CR.sub.2                                                                             H  CH.sub.2CH.sub.3                                                                     H H                  Eptaloprost                                                                         (I)  C C                                                                                    ##STR5##                                                                             O    (CH.sub.2).sub.3                                                                    C CR.sub.2                                                                             H  CH.sub.2CH.sub.3                                                                     H H                  Ciprostene                                                                          (I)  CHCH    n-C.sub.5 H.sub.10                                                                    CH.sub.2                                                                           CH.sub.2                                                                            H        H  --     H CH.sub.3           Beraprost                                                                           (II) CHCH                                                                                   ##STR6##                                                                             CH.sub.2                                                                           CH.sub.2                                                                            C CR.sub.2                                                                             H  CH.sub.3                                                                             H H                  __________________________________________________________________________

The compounds of general formula I or II can be used effectively in thetest below:

Cells from the synovial fluid of patients with chronic polyarthritis areco-cultivated in vitro with 4-day-old limb buds of mouse embryos (12days). After co-cultivation for about 7 days, degradation of thecartilage in the limb buds occurs; this degradation can be reduced inthe presence of the prostane derivatives according to the invention.

The degradation of the cartilage is measured by the release of sulfatedglycosaminoglycans, which are quantified as alcian blueglycosaminoglycan complex.

The prostane derivatives according to the invention reduce the releaseof glycosaminoglycans, in which case the release is induced via thesynovial cells.

Electron microscope examination of cartilage that has been exposed tothe activated synovial cells of patients with chronic polyarthritisshows complete degradation of collagen fibrilla. In the presence ofprostane derivatives according to the invention, the degradation ofcollagen fibrilla is reduced.

The test system shows biochemically and electron-microscopically thatthe cartilage degradation induced by synovial cells of patients withchronic polyarthritis is reduced by the prostane derivatives of formulaI or II according to the invention.

The prostane derivatives according to the invention exhibit the effectin the above-mentioned test at concentrations of 0.1 to 1000 ng/ml. Theabove-mentioned in vitro test system can be imparted to in vivoprocesses (cf.: J. J. STEINBERG et al. (1983) Biochem. Biophys. Acta757: 47-58, further M. J. GROSSLEY and I. M. HUNNEYBALL (1984) Biochem.Pharmac. 33: 1263-1271, further K. KELLER et al. (1990), J. Orthop Res.8: 345-352). The in vitro system is complex, so that it isrepresentative of the clinical picture in chronic polyarthritis.

The compounds of general formula I or II are suitable for the treatmentof chronic polyarthritis.

For this therapeutic effect, the suitable dose differs and depends, forexample, on the compound of general formula I or II that is used, thehost, the type of administration, and the type and severity of theconditions to be treated, but in general, satisfactory results are to beexpected in animals with daily doses of 1 to 3000 μg/kg of animal bodyweight. With large mammals, e.g., humans, there is a recommended dailydose of 0.1 to 200 mg of the prostane derivatives of general formula Ior II according to the invention. Preferred are values of 0.3 to 60 mgper day, more preferred is 1 to 20 mg per day, and most preferred is 2to 10 mg per day. The daily dose of prostane derivatives should beadministered in 2 to 4 partial doses per day.

The prostane derivatives of general formula I or II can be administeredby any usual method in the case of systemic treatment, especiallyenterally, preferably orally, and most preferably parenterally.Suppositories, tablets, capsules, drops, injection solutions, orsuspensions are the appropriate forms for administration.

The prostane derivative iloprost is the especially preferred substance.It is administered, for example, in the case of large mammals, e.g.,humans, in the above-represented type. In this cage, the doses aresmaller by a factor of 2 than was previously indicated. The infusionsolution as a continuous infusion in commonly used aqueous solvents,e.g., physiological common salt solution, is the form of administrationpreferred for systemic treatment. In this case, 0.01 ng/kg/min to 1.0ng/kg/min is administered, preferably 0.03-0.3 ng/kg/min, and mostpreferably 0.1±0.05 ng/kg/min.

Since chronic polyarthritis also manifests itself in intermittentattacks, a prostane derivative is also to be administered during thesymptom-free period. Thus, the prostane derivative according to theinvention is used for prophylactic treatment. The dosages forprophylactic administration do not deviate significantly from thosedescribed above, but values that are lower by a factor of 2 to 4 thanthose that are used in the case of acute attacks are preferred.

This invention also relates to therapeutic compositions that contain aprostane derivative of general formula I or II together with at leastone pharmaceutical vehicle, additive or diluent, which all arephysiologically compatible. Such compositions can be produced in a wayknown in the art. Pharmacologically compatible and suitable adjuvantsand vehicles are described, for example, in Remington's PharmaceuticalScience, 15th ed. Mack Publishing Company, Easton, Pa. (1980). Also, theuse of cyclodextrin clathrates, which are listed in European PatentSpecification EP 0 259 468, is possible.

By contrast with systemic treatment, topical application with a prostanederivative according to the invention, if appropriate with adjuvantsand/or vehicles, is especially preferred.

The cardiovascular action is strongly felt at higher concentrations ofprostane derivatives in the blood. Therefore, it is advantageous toapply the prostane derivatives according to the invention to the skindirectly at the impaired joint. To this end, ointments, pastes, gels, orpacks are suitable. This list is not exhaustive.

With topical application, the concentration of prostane derivatives inthe joint in question is raised to a high value in a desired way, andsimultaneously the concentration of prostane derivatives in the bloodlies practically below the detection limit. The high bio-availability ofthe prostane derivatives results in quick penetration of the skin andthe subjacent connective tissue, and the distribution of the prostanederivatives follows the law of diffusion. On the other hand, transportby convection current plays a completely insignificant role. The vesselsthat lie in or below the skin where the prostane derivatives are appliedare either too small (venules, arterioles) or have too small aneffective surface (veins, arteries) per skin part to cause a noticeableconcentration of prostane derivatives in the blood.

EXAMPLE PART 1

Cell Cultures from Synovial Fluid

Cells from the synovial fluid of patients with chronic polyarthritis areco-cultivated in vitro with 4-day-old limb buds of mouse embryos (12days old). After co-cultivation for about 7 days, degradation of thecartilage in the limb buds occurs, which can be reduced in the presenceof the prostans derivatives according to the invention.

The substance iloprost is present in a final concentration of 100 ng/mlof culture medium in the cell cultures and is to be added to the cellcultures at the start.

Samples are taken on days 1 to 7. The culture conditions are describedin detail in H. MOHAMED-ALI (1991) Z. Rheumatol. 50: 74-81; further inH. J. MERKER (1991) in Culture Techniques, D. NEUBERT and H. J. MERKER(eds.) Walter de Gruyter Verlag, Berlin--New York, pp. 119-133; furtherin H. B. FELL and R. W. JUBB (1977) Arthritis Rheuma 20: 1359-1371.

Instead of iloprost, the control batch contains only culture medium.

EXAMPLE PART 2

Measurement of Cartilage Degradation

Cartilage degradation is measured by the release of sulfatedglycosaminoglycans, which are quantified as alcian blueglycosaminoglycan complex. The release of glycosaminoglycan is describedin P. WHITEMAN (1973) Biochem J 131: 343-351. The samples taken on days1 to 7 show the results listed in Table 2.

                  TABLE 2                                                         ______________________________________                                        Day of Sampling:                                                                             1     3       4   5     6   7                                  ______________________________________                                        Culture with iloprost.sup.1)                                                                  7    13      14  12    11  13                                 Control.sup.1) 11    24      19  22    21  21                                 ______________________________________                                         .sup.1) = Value in μg of glucosaminoglucan per ml of medium           

The prostane derivatives according to the invention reduce the releaseof glycosaminoglycans significantly.

EXAMPLE PART 3

Electron Microscope Evaluation

Electron microscope examination of cartilage that has been exposed tothe activated synovial cells of patients with chronic polyarthritisshows complete degradation of collagen fibrilla. In the presence ofprostane derivatives according to the invention, the degradation ofcollagen fibrilla is reduced.

The production of the electron microscope preparations and thehistological evaluation are described in H. MOHAMED-ALI (1991) Z.Rheumatol. 50: 74-81; further in H. J. MERKER (1991) in CultureTechniques, D. NEUBERT and H. J. MERKER (eds.) Walter de Gruyter Verlag,Berlin--New York, pp. 119-133; further in H. B. FELL and R. W. JUBB(1977) Arthritis Rheuma 20: 1359-1371. In appearance the culture cellsof patients with chronic polyarthritis treated with the prostanederivative according to the invention are approximately midway betweencells from patients with chronic polyarthritis without prostanederivative treatment and cells from patients without chronicpolyarthritis. The reduction of collagen degradation due to thepreparations is estimated at 50%.

I claim:
 1. A method for treating chronic polyarthritis which comprisesadministering to a subject in need thereof, a chronic polyarthritistreatment effective amount of a prostan compound of formula I or II##STR7## in which X₁ is a --CH₂ --CH₂ --; trans --CH═CH-- or a--C.tbd.C-- group,X₂ is a straight-chain or branched, saturated alkylenegroup with 1 to 6 carbon atoms, X₃ is an --O-- or --CH₂ --, X₄ is --CH₂-- or --[CH₂ ]₃ --, X₅ --H or --C.tbd.C--R₂ ; R₁ is a hydrogen atom, analkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 5 or 6carbon atoms, or a phenyl group, R₂ is a straight-chain orbranched-chain, saturated or unsaturated alkyl group with 1 to 6 carbonatoms, R₃ is a hydrogen atom, an acyl radical with 1 to 4 carbon atoms,or a benzoyl radical, and R₄ is an --H or --CH₃ ;in which the --O--R₃group is in α- or β-position, or optionally a salt thereof with aphysiologically compatible base, when R₁ is a hydrogen atom.
 2. Themethod of claim 1, wherein the prostane compound is of the formula I inwhichX₁ is trans --CH═CH--, X₂ is a straight-chain or branched,saturated alkylene group with 2 to 4 carbon atoms, X₃ is --CH₂ --, X₄ is--CH₂ --, X₅ is --C.tbd.C--R₂ ; R₁ is a hydrogen atom, an alkyl groupwith 1 to 3 carbon atoms, or a phenyl group, R₂ is a straight-chain orbranched-chain, saturated or unsaturated alkyl group with 1 to 3 carbonatoms, R₃ is a hydrogen atom or an acyl radical with 2 carbon atoms andR₄ is --H;in which the --O--R₃ group is in α- or β-position, oroptionally a salt thereof with a physiologically compatible base, whenR₁ is a hydrogen atom.
 3. The method of claim 2, whereinX₁ is a trans--CH═CH-- group, X₂ is a methylethylene group in which the methyl groupis connected to the first carbon atom of the ethylene group, X₃ is --CH₂--, X₄ is --CH₂ --, X₅ is --C.tbd.C--R₂ ; R₁ is a hydrogen atom or amethyl group, R₂ is a methyl or ethyl group, R₃ is a hydrogen atom or aformyl group, and R₄ is an --H;in which the --O--R₃ group is in α- orβ-position, or optionally a salt thereof with a physiologicallycompatible base, when Rx is a hydrogen atom.
 4. The method of claim 3,whereinX₁ is a trans --CH═CH-- group, X₂ is a methylethylene group, inwhich the methyl group is connected to the first carbon atom of theethylene group, X₃ is --CH₂ --, X₄ is --CH₂ --, X₅ is --C.tbd.C--R₂ ; R₁is a hydrogen atom, R₂ is a methyl group, R₃ is a hydrogen atom, and R₄is an --H;in which the OH group is in α- or β-position, or optionally asalt thereof with a physiologically compatible base.
 5. The method ofclaim 1, wherein the prostane compound is cicaprost or a salt thereof.6. The method of claim 1, wherein the prostane compound is eptaloprostor a salt thereof.
 7. The method of claim 1, wherein the prostanecompound is ciprostene or a salt thereof.
 8. The method of claim 1,wherein the prostane compound is beraprost or a salt thereof.
 9. Themethod of claim 1, wherein the prostane compound is administered in apharmaceutical composition further comprising pharmacological adjuvantsor vehicles.
 10. The method of claim 1, wherein the subject is a humanor other mammal.
 11. The method of claim 1, wherein the prostanecompound is administered in a composition having a prostane compoundconcentration of 0.1 to 1000 ng/ml.
 12. The method of claim 1, whereinthe prostane compound is administered in a daily dose of 1 to 3000 μg/kgof the subject body weight.
 13. The method of claim 1, wherein thesubject is a human and the prostane compound is administered in a dailydose of 0.1 to 200 mg.
 14. The method of claim 1, wherein the subject isa human and the prostane compound is administered in a daily dose of 0.3to 60 mg.
 15. The method of claim 13, wherein the daily dose isadministered in 2 to 4 partial doses per day.
 16. The method of claim 1,wherein the prostane compound is administered enterally or parenterally.17. The method of claim 1, wherein the prostane compound is administeredtopically.